Fe-Catalyzed Fluoroalkyl(hetero)arylation of Vinyl Azaarenes: Rapid and Modular Synthesis of Unsymmetrical 1,1-Bis(hetero)arylalkanes

In contrast to transition-metal-catalyzed difunctionalization of activated alkenes, selective alkylarylation of vinyl azaarenes is underdeveloped. Consequently, the lack of modular and rapid syntheses of 1,1-bis(hetero)arylalkanes limits their exploration in medicinal chemistry. Herein we report a protocol using commercially available iron salts, bisphosphine ligands, fluoroalkyl halides, and Grignard reagents that enables the selective 1,2-fluoroalkyl(hetero)arylation of vinyl azaarenes. We demonstrate the versatility and robustness of the method through the selective synthesis of a range of unsymmetrical 1,1-bis(hetero)arylalkenes, including pyridine N-oxides, triazoles, pyrazines, carbazoles, indazoles, and 1,2-azaborines. Mechanistic insights from experimental and computational investigations support a radical pathway and provide insights into the role of non-covalent interactions in iron catalysis.

A romatic nitrogen-containing heterocycles are vital scaf- folds in the synthesis of new pharmaceuticals, agrochemicals, and materials. 1Due to their ability to participate in a wide range of intermolecular interactions in biological systems 2 these scaffolds are abundant in FDA-approved smallmolecule drugs, with pyridine being the second most frequently found ring system. 3In this vein, 1,1-diarylalkanes are a common and important motif in pharmaceutical and agricultural chemistry (Scheme 1a). 4,5Traditionally, 1,1diarylalkanes are synthesized through two general reaction types: two-or three-component reactions.In contrast to twocomponent variants, three-component reactions conveniently permit the rapid and modular synthesis of complex molecules through the union of three (often readily accessible) chemical building blocks and thus allow for greater diversity and efficiency.However, the synthesis of 1,1-diarylalkanes through transition-metal-catalyzed three-component dicarbofunctionalization of alkenes has been limited to the use of styrenyl or alkenyl olefins. 6−9 Recently, Guo 10 and Liu 11 reported the use of nickel and copper as catalysts with bipyridine ligands to enable the three-component difunctionalization of vinyl azaarenes to form 1,1-diarylalkenes (Scheme 1b).However, a major drawback of these methods is the use of designed cycloalkylsilyl peroxides as radical precursors in the sole example by Guo.In addition, the requisite for excess aryl and alkyl coupling partners (>3 equiv) and extended reaction times (>72 h) by the Liu group limit applicability in medicinal chemistry.Builing upon prior work in our lab on multicomponent iron-catalyzed cross-coupling reactions, 12 we questioned whether we could use vinyl azaarenes as effective cross-coupling partners in this transformation to access unsymmetrical 1,1-diarylalkenes.
Herein, we report the use of a bisphosphine−iron catalytic system that allowed three-component dicarbofunctionalization of vinyl azaarenes with fluoroalkyl bromides and (hetero)aryl Grignard reagents, leading to the synthesis of previously inaccessible unsymmetrical 1,1-bis(hetero)arylalkanes at low temperatures with short reaction times.
Due to the importance of azaarene compounds, the scope of vinyl azaarenes as radical linchpins in this multicomponent radical cross-coupling reaction was investigated (Scheme 3).Overall, a range of different functionalities of vinyl azaarene compounds were compatible with this transformation, leading to the desired 1,1-diarylalkanes containing quinoline (5a), 2-, 3-, and 4-picolines (5b, 5c, 5d), 2-, 3-, and 4-bromopyridines (5e, 5f, 5g), 4-methoxypyridine (5h), N-alkyltriazole (5i), pyrazine (5j), and pyridine N-oxide (5k) after oxidation of 4a.Remarkably, this work also provides direct access to azaborines (5l).Given the importance of azaborines as isosteres for naphthalenes, we anticipate that this work can expand utility of these systems in medicinal chemistry, and current efforts to develop asymmetric variants are ongoing in our laboratory.Finally, considering recent developments in skeletal editing strategies with pyridines and pyridine oxides, we anticipate that these products can be further derivatized for applications in medicinal chemistry.
of the desired product and Fe(I) species 4 A, which can then initiate the catalytic process again.A proposed catalytic cycle can be found in Figure S13.We also explored an alternative pathway in which the C−C bond is formed through an outersphere mechanism via 4 TS4.Here we found that the pyridine nitrogen can interact with the metal center to facilitate this process. 15However, this pathway is ruled out based on a much higher energy barrier (∼20.1 kcal/mol) compared with the inner-sphere stepwise C−C bond formation.
Next, we redirected our efforts toward using calculations to gain a deeper understanding of nitrogen's crucial role in ensuring the success of this transformation.To accomplish this, we conducted a mechanism calculation using styrene.In Scheme 4c, the thermodynamic drive for the first addition is essentially the same.However, a significant difference was observed in the rate-determining reductive elimination step.Specifically, 4 TS3 for the pyridine system shows a lower energy barrier by approximately ∼4.0 kcal/mol compared to 4 TS3′ for the phenyl system (12.4vs 16.5 kcal/mol; Scheme 4d).Distortion/interaction analysis revealed that the lower barrier associated with 4 TS3 is due to the lower distortion energy (ΔE dis ) between the two fragments compared to that of 4 TS3′ (Scheme 4d).In addition, the natural bond orbital (NBO) analysis showed that 4 TS3 benefits from favorable donor− acceptor interaction energy from the lone pair (LP) in the pyridine moiety with the antibonding (BD*) orbital of the C− H bond on the ligand, supported by the non-covalent interaction (NCI) (Scheme 4e).The efficiency of achieving this weak interaction can be seen in the poor yield obtained with ligands in the absence of alkyl C−H (e.g., dppe).

Table 1 .
C through the selective quartet spin state 4 TS2 (barrier ≈ 3.7 kcal/mol) to form the distorted square-pyramidal Fe(III) intermediate 4 D in the same spin state.Finally, the subsequent and irreversible reductive elimination via selective quartet spin state 4 TS3 (barrier ≈ 12.4 kcal/mol) results in the formation Scheme 1. Importance of 1,1-Diarylalkanes and Current Three-Component Transition-Metal-Catalyzed Dicarbofunctionalizion Strategies to Access These Scaffolds Optimization of the Reaction Conditions